Alcoholism has profound effects on the immune system, including the immune system of the brain. There is evidence that alcoholism increases neuroimmune signaling and inflammation. Alcoholic human brains have increased amounts of neuroimmune signaling molecules, and increasing neuroimmune signaling leads to increased alcohol consumption in animals. There is a possibility that decreasing neuroimmune signaling will lead to decreased alcohol drinking. The proposed experiments will investigate the role of a particular neuroimmune signaling molecule, MCP-1, in an animal model of drinking behavior. We will increase or decrease the amount of MCP-1 signaling in the brain and measure the effect on drinking behavior. There are three phases of drinking behavior we will investigate. First, we will look at the acquisition of drinking behavior (i.e., an animal that has never drunk before will be given increased or decreased amount of MCP-1 signaling and we will measure the ability of the animal to start drinking). Next, we will look at the escalation of drinking behavior (i.e., the animal will increase its drinking over time, and we will increase or decrease the amount of MCP-1 signaling to see if it increases or decreases the amount of alcohol the animal drinks over time). Third, we will look at drinking behavior in an addicted animal (i.e., the rodent will become dependent on alcohol, and then we will increase or decrease the amount of MCP-1 signaling and measure its effect on drinking). Novel aspects of the application include using MCP-1 injections to regulate chronic drinking behavior and using MCP-1 antagonists to regulate either acute or chronic drinking behavior. The mechanisms of addiction are mysterious. The research proposed in this application will provide critical new knowledge about a new area of research and will increase our understanding of addiction. By understanding how neuroimmune signaling can regulate drinking behavior, we can develop insights into the transition from healthy to unhealthy drinking behavior and we can develop new molecular targets for treatment.